The plasma ammonia response to exercise in chronic obstructive pulmonary disease (COPD) was examined and the relationship between plasma ammonia concentration and muscle adenine nucleotide metabolism was explored. In total, 25 stable COPD patients and 13 similar-aged controls underwent incremental and constant-work rate cycle exercise tests. Arterialised venous blood was sampled at rest, at 1-min intervals during exercise and <or=5 min after exercise for ammonia and lactate concentration. Peak incremental work rate was significantly less in COPD subjects (67+/-21 W) than similar-aged controls (156+/-46 W). In COPD and control subjects, plasma ammonia concentration increased during incremental exercise until 2 min post-exercise and then declined by 5 min post-exercise. However, two distinct patterns were seen in COPD subjects. In one group (n = 16), ammonia increased (42.8+/-3.3 micromol x L(-1)) by a similar magnitude as the controls (55.5+/-7.0 micromol x L(-1)). In the second COPD group (n = 9), no ammonia increase was observed despite a similar lactate increase. Ammonia change with incremental and constant-work rate exercise strongly correlated in COPD subjects. Plasma ammonia increase correlated with muscle inosine-5'-monophosphate formation after constant-work rate exercise. Plasma ammonia concentration increases during incremental and constant-work rate cycle exercise in chronic obstructive pulmonary disease subjects at lower absolute work rates compared with similar-aged controls. The plasma ammonia response may provide useful information about adenine nucleotide metabolism and, therefore, muscle fatigue during exercise in patients with chronic obstructive pulmonary disease.